DESCRIPTION (Adapted from the application) The candidate's goals are to pursue a career in academic pediatric nephrology. He will perform research under the guidance of a world- renowned basic scientist in the area of developmental biology. He will have access to state-of-the-art facilities and technical support while in the laboratory. He will be in a Pediatrics Department, which has already shown commitment to giving him protected research time when he was a fellow. The candidate will pursue a career development plan that will ultimately lead to his being a successful independent investigator. He will acquire new skills in molecular biology and enhance existing skills. He will have contact with other professors who have extensive backgrounds in molecular and developmental biology. He is also at a university which host lectures from eminent basic scientists from around the world. The long term objectives of the research project are to decipher the role of the insulin receptor-related receptor (IRR) in the kidney. IRR is a novel receptor tyrosine kinase with expression in non-A intercalated cells in the kidney. Intercalated cells serve as integral component of the kidney's defenses against perturbation in systemic pH. The developmental origin of the intercalated cells is unknown. The mechanisms by which mature I intercalated cells are activated to secrete acid or B (non-A) cells to secrete base are unknown. A receptor tyrosine kinase such as IRR would be a likely candidate to mediate either the development and/or metabolic regulation of intercalated cells, especially non-A cells. Deciphering the developmental and systemic regulation of intercalated cells could lead to an understanding and ultimately a cure for acid/base disorders such as renal tubular acidoses. The specific aims of the project are: 1. To determine the developmental origin of intercalated cells. 2. To establish whether IRR is an embryological determinant of non-A intercalated cells. 3. To determine if IRR affects phenotypic changes which occur in intercalated cells in response to changes in systemic perturbations. An IRR-green fluorescent protein fusion will be integrated into the genome in replacement of endogenous IRR to follow developmental tracking of non-A intercalated cells. If IRR-null mice have alterations in intercalated cells, IRR-null embryonic kidney explants will be infected with an IRR expression vector in an attempt to rescue the phenotype. Effects of forced over expression of IRR in normal kidney tissues will also be examined. After being subjected to systemic alkalosis, IRR-null mouse kidneys will be examined to determine if the intercalated cells have appropriately altered their morphology and intracellular distribution of proton transporters.